This project is devoted to an exploration of the biochemical mechanisms underlying enzyme regulation in differentiating tissues. Factors controlling the initial emergence of enzymes and their subsequent developmental courses will be under study, with hope of contributing to the understanding of genetic and developmental abnormalties in man. The postnatal development of histidase (L- histidine ammonia-lyase) in the rat will serve as a model system. This enzyme initially appears in liver and epidermis at parturition and undergoes a further complex developmental course specific to each tissue. We have already demonstrated that histidase is responsive to many hormonal stimuli, competence to respond to a particular hormone being acquired or lost as development proceeds. Certain hormones, furthermore, seem to be determinative at critical stages of development. We will now plan to probe into the intimate molecular mechanisms underlying hormonal influences during peri- and postnatal development of histidase in liver and epidermis. This will be accomplished by: development of cell or organ culture systems in which hormonal control of histidase may be studied in vitro; exploration of the formation of possible enzyme variants during development, under hormonal influence, and at different tissue sites; purification of histidase and preparation of its antibodies. Using the foregoing as a base, we will continue investigation of the mechanisms of pituitary suppression of this enzyme and its relationship to estrogenic induction and will study, in in vitro and in vivo systems, rates of enzyme protein and RNA synthesis and degradation during development and hormonal control of histidase in liver and epidermis. Finally, we will initiate a study of the influences of maternal malnutrition, prior to and during pregnancy, on the postnatal development of histidase and other enzymes, in order to explore some of the parameters responsible for failure of neo- and postnatal metabolic competence.